title: Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.
abstract: Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors -inexpensive drugs with decades of safe use - could be rapidly repurposed as cancer therapeutics.
authors.affiliation: 1] Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA [3].
authors.forename: Vikash P
authors.initials: VP
authors.lastname: Chauhan
authors.forename: John D
authors.initials: JD
authors.lastname: Martin
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Delphine A
authors.initials: DA
authors.lastname: Lacorre
authors.forename: Saloni R
authors.initials: SR
authors.lastname: Jain
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozin
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Stylianopoulos
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Mousa
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Han
authors.forename: Pichet
authors.initials: P
authors.lastname: Adstamongkonkul
authors.forename: Zoran
authors.initials: Z
authors.lastname: Popović
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.forename: Moungi G
authors.initials: MG
authors.lastname: Bawendi
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000809:Angiotensins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D058492:Drug Repositioning; D004357:Drug Synergism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D040542:Mechanotransduction, Cellular; D051379:Mice; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000809:Angiotensins; D000970:Antineoplastic Agents; C526318:CCN2 protein, mouse; D019332:Endothelin-1; D044140:Receptor, Angiotensin, Type 1; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D006820:Hyaluronic Acid; D003094:Collagen; D019808:Losartan; D005472:Fluorouracil